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Skin nontumor

General

Histology

Author: Mariantonieta Tirado, M.D.

Editorial Board Member: Robert E. LeBlanc, M.D.

Editor-in-Chief: Debra L. Zynger, M.D.

Last author update: 29 September 2020

Last staff update: 19 July 2021

Copyright: 2002-2024, PathologyOutlines.com, Inc.

PubMed Search: Skin[TIAB] histology[TI] review[PT]

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Table of Contents

Cite this page: Tirado M. Histology. PathologyOutlines.com website. https://www.pathologyoutlines.com/topic/skinnontumorgeneral.html. Accessed May 8th, 2024.

Definition / general

Membrane covering the exterior of the body composed of epidermis and dermis

Essential features

Skin is the largest organ of the body with a weight of approximately 5 kg and an area close to 2 m²
General functions of the skin:
- Protection (against UV light, dehydration, microbial invasion, mechanical injury, chemical and thermal stresses)
- Retains water and excretes drugs and waste
- Thermoregulation through blood vessels and eccrine glands
- Metabolic: vitamin D production
- Sensorial: contains peripheral endings of sensory nerves

Terminology

Also called integument

Physiology

Epidermis
- Outer stratified squamous epithelium composed of epidermal and intraepidermal adnexal (acrotrichial and acrosyringeal) keratinocytes
- Main purpose is cornification
- Keratinocytes are connected by desmosomes, adherens junctions, tight junctions and gap junctions
- Basal layer
  - 10% are stem cells
  - Produces keratin 5
- Squamous layer
  - Desmosomes develop and composition of keratin intermediate filaments change (↑ intracellular calcium)
  - Produces keratins 1 and 10
  - Langerhans cells and Merkel cells present
- Granular layer
  - Profilaggrin which forms filaggrin: facilitates filament aggregation
  - Loricrin and involucrin: contribute to the formation of the insoluble cell envelope
  - Cells begin to lose nuclei
  - Production of the cell envelope
    - Located beneath the cell membrane
    - Composed of crosslinked proteins dependent on transglutaminase
  - Odland bodies
    - Lipid rich lamellated granules (mainly ceramide) secreted into intercellular spaces
    - Contribute to permeability barrier
- Cornified layer
  - Formed because of keratinocytic maturation (cells flatten as they ascend to the surface)
  - Synthesis of lamellar granules and proteins
  - Cells lose their nuclei, cytoplasmic organelles, metabolic activity and eventually desquamate
Dermal epidermal junction: components bind the epidermis to the dermis
- 4 major structural regions proceeding from the epidermis to the dermis
  - Basal cell plasma membrane
  - Lamina lucida: low electron density region, contains laminins (major laminin 332)
  - Lamina densa: electron dense region; its major component is collagen IV
  - Sublamina densa: upper papillary dermis contains loops of type VII collagen (anchoring fibrils)
- Attachment structures
  - Hemidesmosomes: plaque proteins extend from basal plasma membrane of the keratinocyte to the lamina lucida (associated to the anchoring filaments)
  - Anchoring filaments: thread-like structures that cross the lamina lucida
  - Anchoring fibrils: extend from the lower lamina densa to the upper reticular dermis
- Total epidermal renewal time, approximately 2 months
  - Cells take 26 - 42 days to transit from the basal layer to the granular layer
  - 14 days for keratin layer to be shed
Melanocytes
- Neural crest derived dendritic cells that synthesize melanin
- Melanin absorbs ultraviolet (UV) and protects from damaging UV Induced mutations
- Melanin (produced from tyrosine) is transferred in melanosomes (lysosome type organelle), through melanocytic dendritic processes into adjacent keratinocytes and hair shafts
- 2 types of melanin are produced: pheomelanin (yellow-red) and eumelanin (black-brown)
- Racial skin color is due to amount of melanin in keratinocytes, not number of melanocytes
Dermis
- Mainly supports the epidermis and plays varied other roles due to the presence of vessels, nerves and adnexa
- Blood vessels provide nutrients and help regulate temperature
- Sucquet-Hoyer canals
  - Specialized acral arteriovenous anastomoses
  - Allow blood shunting from arterioles to venules, bypassing capillaries
  - Surrounded by modified smooth muscle glomus cells (latter function as sphincters)
  - Primary function is of thermoregulation
- Lymphatics
  - Play a role in tumor spread and removal of debris (fluid, cells and macromolecules)
  - Represent the primary route for Langerhans cells to reach regional lymph nodes
- Nerves
  - Somatic sensory nerves mediate pain, itch temperature and touch
  - Autonomic motor nerves mediate vascular tone, pilomotor response and sweating
  - Afferent nerves consist of myelinated and nonmyelinated free nerve endings
  - 2 types of sensory receptors are present
    - Specialized (encapsulated): Meissner corpuscles have tactile function and Pacinian corpuscles detect pressure
    - Unspecialized: sensory non-encapsulated nerves linked to Merkel cells
Subcutis
- Plays a role in cushioning, insulation, endocrine function and energy stores
- 2 types of fat:
  - White
  - Brown: mostly present in infants and children, rich in mitochondria and produces heat
Adnexa
- Skin associated structures each with specific functions including hair follicles, sebaceous glands, eccrine sweat glands and apocrine glands
- Folliculosebaceous apocrine units: functional complex of hair follicle, sebaceous gland, erector pili muscle and (depending on site) apocrine gland
Hair follicle
- Functions include temperature regulation, protection of other structures and tactile sensory input
- Types of hair
  - Lanugo: present during late gestation and first month of life
  - Vellus: fine hair (face, trunk and extremities)
  - Terminal: coarse (scalp, eyebrows, eyelashes)
- Cycle of hair
  - Anagen: growing phase (lasts 2 - 7 years)
  - Catagen: involuting phase (lasts 2 - 3 weeks, 1 - 2% of total hair)
  - Telogen: resting phase (lasts 100 days, 10 - 20% of total hair)
Sebaceous glands
- Main function is protection by production and release of sebum
- Secretion (governed by androgens) plays a role in waterproofing, control of epidermal water loss and inhibition of fungal and bacterial growth
- Glands are holocrine (secretion depends on degeneration of acini with release of cells and lipid)
- Sebaceous secretions (sebum) carry to the surface a mixture of fat, corneocytes and normal flora (yeasts, bacteria and mites)
- Flora includes Propionobacterium acnes, Staphylococcus epidermidis and Demodex brevis
Apocrine sweat glands
- Concentrated in axilla, groin, perineum, face, periumbilical, external auditory meatus, eyelid and areola
- Function in humans is unknown; in other mammals they produce scent and play a role in sexual attraction
- Odorless secretion is initially released and then modified by superficial bacteria producing body odor
Eccrine sweat glands
- Regulate body temperature
- Present almost everywhere in the skin except oral lips, clitoris, labia minora and external auditory canal
- Eccrine duct possesses a conduit and metabolic (modifies secretion and reabsorbs water) function
- Possess merocrine secretion
Nail unit
- Protects tissues of the distal fingertip from injuries and enhances delicate movements by counterpressure
Langerhans cells
- Bone marrow derived dendritic cells, described in 1868 by Paul Langerhans, a German pathologist, physiologist and biologist (Am J Dermatopathol 1985;7:347)
- Function as intraepidermal macrophages phagocytosing antigens and then migrate to regional lymph nodes where they present antigens to T cells
Merkel cells
- Part of the affector limb mechanoreceptors related with touch sensation
- Described by in 1875 by Friedrich Merkel a Germany anatomist and histopathologist (Am J Dermatopathol 1982;4:521)
- Located in the basal epidermis and concentrated in tactile areas of hairy skin, glabrous skin, lips, eccrine sweat glands and anal canal
- Their close relation with nerve fibers represents a Merkel cell neurite complex
- Heavily granulated cells containing keratin filaments and neuropeptides (Anat Rec A Discov Mol Cell Evol Biol 2003;271:225)

Diagrams / tables

Contributed by Mariantonieta Tirado, M.D.

Normal nail anatomy

Microscopic (histologic) description

Epidermis
- Composed of 4 layers
  - Basal cell layer (stratum basale)
  - Prickle cell layer (stratum spinosum or Malpighian layer)
  - Granular cell layer (stratum granulosum)
  - Corneocyte layer (stratum corneum, horny layer)
- Basal layer
  - Proliferating cell population with cuboidal shape, larger nuclei, conspicuous nucleoli and basophilic cytoplasm
  - Few mitotic figures may be present
  - Melanocytes surrounded by clear halo are present
  - Toker cells are clear cells present in the basal and suprabasal layers of the nipple epidermis of both males and females
- Squamous layer
  - Several layers of larger eosinophilic polygonal cells with oval nuclei and conspicuous nucleoli
  - Cells attached to each other by spine-like processes (intercellular bridges)
- Granular layer: 3 layers of flattened, diamond shaped cells with keratohyaline granules
- Cornified layer: composed of flat, eosinophilic corneocytes without nuclei
- Stratum lucidum
  - Homogenous eosinophilic zone
  - Present only in soles and palms, between granular and cornified layer
Melanocytes
- Appear as clear cells (truly an artifact of fixation, secondary to shrinkage of the cytoplasm), with dendritic cytoplasm and a smaller and more basophilic nucleus than that of a basal keratinocyte
- Ratio of melanocytes to basal cells ranges from approximately 1:4 on the cheek to 1:10 on the limbs
Dermis and subcutis
- Divided into superficial papillary dermis and deeper reticular dermis
  - Papillary dermis: thin collagen fibers, located beneath the epidermis and around adnexa
  - Reticular dermis: thicker, extends from the base of the papillary dermis to the surface of the subcutis
- Varies in thickness depending on anatomic location (eyelid: 0.5 mm; back: 5 mm)
- Consists of connective tissue composed of collagen, elastic fibers and ground substance of mucopolysaccharides and mucoproteins
- Harbors:
  - Scattered cells (fibrocytes, dendrocytes, histiocytes, mast cells, Langerhans cells and rare lymphocytes)
  - Adnexa
  - Smooth muscle
  - Nerves
  - Vessels: small arteries, arterioles and lymphatics
- Small arteries, arterioles, venules, lymphatics and nerves conform a network of 2 connected plexuses parallel to the surface
  - Superficial plexus: located in the upper reticular dermis, supplies the papillary dermis with a capillary loop system
  - Deep plexus: located in the lower reticular dermis
  - Sensory receptors
    - Meissner corpuscles: ellipsoid lamellated structures, localized in the papillary dermis of lips, palms and soles
    - Pacinian corpuscles: ovoid structure with concentric lamellae, localized in the deep dermis and subcutis of genitalia, lips, palms and soles
- Subcutis
  - Contains lobules of mature adipose tissue divided by thin connective tissue septa
  - Composed of adipocytes with a single globule of lipid that compresses the nucleus to the periphery
Hair follicles
- Segments of the hair follicle in longitudinal sections
  - Upper segment: stationary
    - Infundibulum: from ostium of the follicle to the opening of the sebaceous duct; shape of a funnel with similar layers as the epidermis, with granular layer
    - Isthmus: from the opening of the sebaceous duct to the attachment of the arrector pili muscle at the hair bulge; contains a basal layer, spinous layer, absence of granular layer and an eosinophilic cornified layer
  - Lower segment: transient
    - Stem: from base of the isthmus to Adamson fringe (latter area between anucleated cells of the stem and nucleated cells of the bulb)
    - Bulb: contains matrix cells with large pale nucleus and prominent nucleoli and melanocytes that surround the dermal papillae
- Layers of a terminal anagen hair follicle of the suprabulbar area in horizontal sections, from the center to the periphery
  - Hair shaft (medulla, cortex and cuticle)
  - Inner root sheath
    - Cuticular layer of the inner root sheath: 1 cell thick
    - Huxley layer: 2 cells thick with abundant eosinophilic trichohyalin granules
    - Henle layer: 1 cell thick, bright eosinophilic trichohyalin granules
  - Outer root sheath: composed of clear keratinocytes and keratohyaline granules
  - Vitreous and external fibrous layer (perifollicular connective tissue sheath)
- Hair often contains Demodex folliculorum mites, clumps of Staphylococcus epidermidis or Pityrosporum yeasts
Sebaceous glands
- Lobulated structures mostly connected to hair follicles
- Distributed all over the skin with exception of palms, soles and dorsum of the feet
- Have outer cuboidal or flattened, basophilic germinative cells that differentiate, move inward and accumulate intracytoplasmic lipid droplets, causing multivacuolation and indentations of nuclei
- Excretory ducts are lined by keratinizing squamous epithelium
Apocrine sweat glands
- Empty into the follicle above the sebaceous duct
- Includes 2 components
  - Secretory
    - Located in the deep dermis or subcutis
    - Possesses an outer layer of myoepithelial cells and an inner layer of cuboidal to columnar eosinophilic cells
    - Shows luminal "decapitation" secretion
  - Ductal
    - Connects with the pilosebaceous follicle
    - Composed by a double layer of cuboidal cells
    - Histologically indistinguishable from eccrine ducts
Eccrine sweat glands
- Includes 2 components
  - Secretory
    - Located deep in the dermis or subcutis
    - Has an outer layer of myoepithelial cells
    - Also possesses an inner layer of large clear pyramidal cells (secrete water) and smaller darker cells (secrete glycoproteins, mostly line the luminal surface)
  - Ductal
    - Opens directly into the epidermis
    - Composed of a double layer of basophilic cuboidal cells
    - Luminal surface is lined by an eosinophilic cuticle
    - Divided in 4 subunits: coiled secretory unit, coiled dermal duct, straight dermal duct, coiled intraepidermal duct (acrosyringium)
Nail unit
- Comprised of the nail plate and surrounding tissues
- Located in the dorsal aspect of the distal phalanx of fingers and toes
- Anatomic structures include
  - Proximal nail fold: layer that extends superficially with the skin and deeply with the nail matrix
  - Eponychium (cuticle): cornified layer of the nail fold located between the nail plate and matrix
  - Nail matrix: produces the superficial and ventral portions of the nail plate
  - Lunula: white crescent shaped area representing the junction between the matrix and the bed
  - Nail plate: consists of corneocytes and is attached to the nail bed
  - Nail bed: epithelium lying over a vascularized dermis that provides support to the nail plate
  - Hyponychium: intermediate epithelium between the junction of the distal ventral edge of the free nail and the fingertip skin
  - Lateral nail folds: lateral overhanging skin folds that guide the growth of the nail plate
Langerhans cells
- Dendritic cells with reniform nucleus scattered in the superficial epidermal spinous layer into the granular layer and in the dermis, difficult to see on H&E
Merkel cells
- More common in outer root sheath of hair follicles and tactile hair discs
- Not identified with H&E but with immunohistochemistry and electron microscopy

Microscopic (histologic) images

Contributed by Mariantonieta Tirado, M.D.

Layers of the epidermis

Melanocytes

MelanA+ melanocytes

HMB45+ melanocytes

Stratum lucidum

Superficial and deep neurovascular plexuses

Pacinian corpuscle

Meissner corpuscles

Brown fat

Segments of hair follicle

Layers of terminal anagen hair follicle

Demodex folliculorum mites

Sebaceous gland

Adipophilin+ sebaceous gland

Eccrine gland, myoepithelial cell

Eccrine duct

Intraepidermal portion of eccrine duct (acrosyringium)

Apocrine gland

Apocrine gland with decapitation secretion

CD1a+ Langerhans cells

CK20+ Merkel cell

Positive stains

Basal keratinocytes: CK5 / CK14
- Suprabasal: CK1 / CK10
- Palmoplantar suprabasal epidermis: CK9
Toker cells: CK7, AE1, CAM5.2, EMA, HER2, ER and PR (Am J Dermatopathol 1995;17:487, Hum Pathol 2008;39:1295)
Melanocytes: Fontana-Masson, tyrosinase, S100, SOX10, MelanA / MART1, MITF, HMB45, CD117, p75 (Dermatoendocrinol 2011;3:32)
Dermal dendrocytes: factor XIIIa and CD34
Adipocytes and nerves: S100
Vascular
- Arteries, arterioles and veins: alpha smooth muscle actin, CD31 (endothelial) and CD34 (endothelial)
- Lymphatics: D2-40
Hair follicle: outer root sheath
- Upper portion: CK5 / CK14, CK1 / CK10 and CK6 / CK16
- Lower portion: CK5 / CK14 / CK17
Sebaceous glands
- EMA
- Adipophilin (membranous staining of intracytoplasmic lipid droplets) (Mod Pathol 2010;23:567)
- Factor XIIIa (AC‐1A1) (J Cutan Pathol 2016;43:649)
Eccrine and apocrine glands
- Secretory component: CAM5.2 (both cytoplasmic and membranous), EMA (luminal and intercellular canaliculi), BerEP4 (eccrine glands, luminal accentuation), SOX10 (J Cutan Pathol 2017;44:544)
- Ductal component: EMA, CEA (luminal border and lumina)
Myoepithelial cells: actin, calponin, caldesmon, S100, SOX10 (J Cutan Pathol 2014;41:353)
Langerhans cells: S100, CD1a, CD207 (Langerin)
Merkel cells: CK20 (dot pattern), CK8, CK8/18, neuron specific enolase, neurofilament, synaptophysin

Negative stains

Toker cells
- Mucicarmine and PAS (Cancer 1970;25:601)
- p53 or CD138 (Hum Pathol 2008;39:1295)

Electron microscopy description

Melanosomes: spherical membrane bound particle with periodic longitudinal concentric lamellae
Birbeck granules (rod shaped structure with zipper-like striations, often with bulbous end)

Electron microscopy images

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